The invention relates to a process for simultaneously N(2)-acylating piperazic acid or an ester thereof and forming a bicyclic ring structure. The invention also relates to the use of that process step in a method of synthesizing a bicyclic compound useful as an intermediate for the production of an inhibitor of a caspase, particularly an inhibitor of interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d).
Compounds containing a bicyclic aza-containing ring systems have been prepared as conformationally restricted dipeptide surrogates for a variety of medically important compounds. In particular, such ring systems are present in angiotensin converting enzyme (ACE) inhibitors, such as Cilazapril(copyright), and in caspase inhibitors, such as inhibitors of interleukin-1xcex2 converting enzyme (ICE).
Current methods for synthesizing compounds containing these byciclic aza-containing ring systems have many disadvantages. The typical methods of forming this ring system have been described [EP 94,095, WO 95/35308, WO 97/22619, U.S. Pat. Nos. 5,656,627, 5,716,929 and 5,756,486 and J. P. Kim, et al., Tetrahedron Letters, 38, pp. 4935-4938 (1997)].
These methods involve multiple steps wherein an N(1)-protected piperazate must be provided. An appropriately protected amino acid, usually a xcex3-ester of glutamic acid, is coupled to the piperazate. After deprotection, the bicyclic system is then formed via an acid chloride coupling at the N(1) position.
The main disadvantages to such methods are the use of expensive reagents and the number of steps required for protection and deprotection making the overall process extremely time consuming. Moreover, these methods are often useful for research purposes but are not amenable to large scale production.
In order to be more commercially feasible, it would be desirable to produce compounds containing a byciclic aza-containing ring system in an easier, less expensive manner than has been previously described.
Applicant has solved this problem by providing a new method of simultaneously N(2)-acylating an N(1)-protected piperazic acid or an ester thereof and creating a bicyclic ring structure comprising that acylated piperazic acid or ester. Until now, formation of said bicylcic compound had not been achieved via N(2)-acylation.
This method involves the formation of the desired bicyclic system in two simple steps. This method also utilizes inexpensive reagents, require no selective protection/deprotection and is amenable to large scale production. Moreover, this method produces very little contaminating by-products. And this method preserves chirality between the N(1)-protected piperazic acid or an ester thereof and the resulting byciclic aza-containing ring system.
This method is particularly useful for producing an intermediate that may be subsequently converted into a caspase inhibitor, particularly an inhibitor of ICE, through additional steps known in the art.
The following abbreviations are used throughout this application:
t-Bu=tert-butyl
Et=ethyl
Cbz=carboxybenzyl
DMF=N,N-dimethylformamide
THF=tetrahydrofuran
MTBE=methyl tert-butyl ether
DCC=dicyclohexylcarbodiimide
EDC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Ac=acetyl.
DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene
Fmoc=9-Fluorenylmethoxycarbonyl
According to one embodiment, the invention provides a process for converting compound G to compound H: 
wherein:
R1 is a C2-4 straight chain alkyl substituted at the carbon alpha to the COOH moiety with N(R4)(R4), NO2 or N3 and optionally substituted at any other carbon with one or more substituents independently selected from C1-6 straight or branched alkyl, C2-4 straight or branched alkenyl or alkynyl, Oxe2x80x94[C1-6 straight or branched alkyl], Oxe2x80x94[C2-6 straight or branched alkenyl or alkynyl], oxo, or halo; wherein
each R4 is independently selected from H or an amino protecting group, with the proviso that both R4 are not simultaneously hydrogen;
R2 is selected from hydrogen, C1-6 straight or branched alkyl, C2-6 straight or branched alkenyl or alkynyl, or Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar; wherein
Ar is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S; and
Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from C1-6 straight or branched alkyl, C2-6 straight or branched alkenyl or alkynyl, Oxe2x80x94[C1-6 straight or branched alkyl], Oxe2x80x94[C2-6 straight or branched alkenyl or alkynyl], oxo, halo, NO2, N(R4)(R4), or CN;
n is 0 or 1;
any substitutable ring carbon is optionally substituted by Q1; wherein
each Q1 is independently selected from xe2x80x94Ar1, xe2x80x94T1xe2x80x94R9, or (CH2)1-3xe2x80x94T1xe2x80x94R9; provided that when xe2x80x94Ar1 is substituted with a Q1 which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1; wherein
Ar1 is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S; and
wherein each Ar1 is optionally singly or multiply substituted at any ring atom by xe2x80x94N(R9)(R9), halo, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
xe2x80x83or xe2x80x94Q1;
wherein each R9 is a C1-6 straight or branched alkyl group optionally substituted with one or more substituents independently selected from xe2x80x94F, xe2x95x90O or Ar1, wherein any R9 may be substituted with a maximum of two Ar1;
T1 is selected from a valence bond, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR10xe2x80x94, Oxe2x80x94C(O)xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94NR10xe2x80x94, xe2x80x94S(O)2xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94S(O)2xe2x80x94, or xe2x80x94NR10xe2x80x94S(O)2xe2x80x94NR10xe2x80x94; and
each R10 is independently selected from xe2x80x94H or C1-6 straight or branched alkyl;
The term xe2x80x9camino protecting groupxe2x80x9d, as used herein, means a moiety that prevents chemical reactions from occurring on the nitrogen atom to which that protecting group is attached. An amino protecting group must also be removable by a chemical reaction. Amino protecting groups that are acid cleavable include t-butoxycarbonyl. Examples of amino protecting groups that are base cleavable include Fmoc and alkyl carbamates. Amino protecting groups that are cleaved by hydrogenolysis include Cbz and allyloxycarbonyl. The phthalimide protecting group is typically removed by treatment with hydrazine.
In a preferred embodiment, R1 is substituted at the terminal carbon (i.e., the one bound to the N(1) ring nitrogen) with oxo, making R1 an acyl-containing moiety. More preferred is when R1 contains both the protected amine substituent and the oxo substituent. One of the most preferred R1 groups is: 
In another preferred embodiment, n is 1.
In yet another preferred embodiment, R2 is t-butyl.
The method of this invention comprises the steps of:
(a) combining compound G with an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme, THF, or CCl4;
(b) adding less than about 0.2 equivalents of DMF;
(c) adjusting the temperature of the resulting mixture to between 20xc2x0 C. and 100xc2x0 C.;
(d) adding about 2 or more equivalents of SOCl2 to said mixture over a period of between 2 and 24 hours.
Not all organic solvents may be used in step (a). The list of solvents set forth above are known to work. Other similar organic solvents may also work in the reaction and are to be considered part of the present invention. Preferably, the organic solvent is toluene or dichloroethane.
In step (b), it is preferred to use about 0.1 equivalent of DMF. Step (c) is preferably carried out at about 60xc2x0 C. In step (d), it is preferred to use about 2 equivalents of SOCl2 as a solution in toluene or dichloroethane. It is also preferred that the solution of SOCl2 be added slowly over a period of about 2 hours. Addition of the SOCl2 solution over less than 2 hours tends to drastically reduce the efficiency of the reaction.
According to another preferred embodiment, about 5 equivalents of base are added to the reaction at step (b). Preferably, the base is selected from pyridine, collidine, lutidine, NaHCO3, imidazole, triethylamine, N-methylmorpholine, diisopropylethylamine or K2CO3. Most preferably, the base is 2,6-lutidine.
Once the SOCl2 solution has been added, the reaction is complete. At that point compound H may be isolated by standard procedures, such as diluting the reaction with an organic solvent and then washing the solution first with NaHCO3 and then with brine, followed by drying over Na2SO4 and concentrating.
The conversion of compound G to compound H requires cyclization to occur at the N(2) position. This reaction is seemingly amenable to standard conditions well known in the art for forming an acid chloride intermediate. However, we determined that treating compound G with the known acid chloride forming reagents PCl5, oxalyl chloride, and SOCl2 under conditions well known in the art formed little or no desired product H.
Such well known reaction conditions include combining the starting compound with solvent, typically dichloromethane, and adding 1 equivalent or more of the acid chloride forming reagent (e.g. SOCl2, PCl5, or oxalyl chloride) at various temperatures. The details of the conditions used for some of these reactions are set forth in the examples. Such standard conditions were ineffective in converting compound G to desired compound H. Without being bound by theory, we believe that the method of converting compound G to compound H as set forth herein does not proceed via an acid chloride intermediate.
Extensive experimentation was required to achieve the reaction conditions of this invention. The results of these experiments were highly variable and yields varied greatly depending upon the specific conditions used. Only the method of this invention achieved the conversion of compound G to compound H in high yield ( greater than 75%) and purity.
Compound G may be obtained through standard synthetic routes well-known in the art. One such route is depicted below. Scheme 1 depicts the creation of intermediate E. 
In Scheme 1, xe2x80x9cHalxe2x80x9d is any halogen; n and R2 are as defined above; and each Rxe2x80x2 is an independently selected carboxyl protecting group. Examples of suitable Rxe2x80x2 include, but are not limited to, alkyl, alkenyl, aryl, and aralkyl groups. Each of these steps is well-known in the art. Specifics concerning the conditions and reagents used at each step are set forth in the Examples.
The conversion of intermediate E to compound G is set forth in Scheme 2, below. That conversion may be achieved in either one of the two ways depicted in Scheme 2, depending upon the nature of R1. 
In Scheme 2, Rxe2x80x2, R1, and R2 are as defined above. Reaction 4A comprises simultaneous deprotection of E and acylation if the amine protecting groups can be removed by hydrogenolysis, e.g., if the protecting group is Cbz. If not, a deprotection step must precede the addition of the anhydride F for the acylation reaction.
In order to completely deprotect at both nitrogens under transfer hydrogenation conditions, at least 2 equivalents of a proton donor (e.g., Et3SiH) must be added. If only one equivalent of the proton donor is added, deprotection occurs selectively at the N(2) nitrogen: 
The resulting N(1) protected compound, M, is also useful as an intermediate in producing medically important compounds, such as the ICE inhibitors described herein and in PCT publications WO 97/22619 and WO 95/35308. Thus, this reaction to produce an N(1) protected compound is also an embodiment of the present invention.
When compound F contains substituents and is not symmetrical, reaction 4A may produce mixtures of compounds, wherein acylation of the N(1) nitrogen may occur at either C(O) functionality. This may be avoided by using substituents that favor the formation of the desired product. For example, in reaction 4A, the use of: 
as compound F directs the formation of a compound wherein acylation of the N(1) nitrogen occurs at the C(O) functionality furthest away from the phthalimide substituent [J. A. Elberling, et al, Organic Preparations and Procedures Int., pp. 67-70 (1978)].
Reaction 4B depicts the formation of G from intermediate E in a stepwise manner. The two carboxy protecting groups (Rxe2x80x2) on compound E may be different, such that the N(1) protecting group (xe2x80x94COORxe2x80x2) can be selectively removed without removing the N(2) protecting group. Compound F can then be coupled at the N(1) position to afford compound E-1. Deprotection of the carboxyl protecting group affords compound G. Each of these steps is well known in the art. Specifics concerning the conditions and reagents used at each step are set forth in the Examples.
Intermediate compound G, and its subsequent conversion to compound H, may serve as the key intermediate and synthesis step, respectively, in an improvement in the synthesis of known caspase inhibitors, particularly inhibitors of interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d), such as those described in U.S. Pat. Nos. 5,716,929, 5,656,627, and 5,756,466 and in PCT publications WO 95/35308 and WO 97/22619.
Those inhibitors have the general formula (I): 
wherein:
any ring is optionally substituted at any carbon by Q1, at any nitrogen by R5, and at any atom by xe2x95x90O, xe2x80x94OH, xe2x80x94COOH, or halogen;
X1 is CH or N;
g is 0 or 1;
m and mxe2x80x2 are independently 0, 1 or 2;
n is 0 or 1;
each J is independently selected from xe2x80x94H, xe2x80x94OH, or xe2x80x94F, provided that when a first and a second J are bound to a C, and said first J is xe2x80x94OH, then said second J is xe2x80x94H;
T is xe2x80x94Ar3, xe2x80x94OH, xe2x80x94CF3, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94OH, xe2x80x94C(O)xe2x80x94OH or any biosteric replacement for xe2x80x94C(O)xe2x80x94OH;
R3 is xe2x80x94CN, xe2x80x94CHxe2x95x90CHxe2x80x94R9, CHxe2x95x90Nxe2x80x94Oxe2x80x94R9, xe2x80x94(CH2)1-3xe2x80x94T1xe2x80x94R9, xe2x80x94CJ2xe2x80x94R9, xe2x80x94C(O)xe2x80x94R13, or xe2x80x94C(O)xe2x80x94C(O)xe2x80x94N(R5)(R10);
T1 is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR10xe2x80x94, Oxe2x80x94C(O)xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NR10xe2x80x94C(O)xe2x80x94NR10xe2x80x94, xe2x80x94S(O)2xe2x80x94NR10xe2x80x94, xe2x80x94NR10xe2x80x94S(O)2xe2x80x94 or xe2x80x94NR10xe2x80x94S(O)2xe2x80x94NR10xe2x80x94;
each R5 is independently selected from xe2x80x94H, xe2x80x94Ar1, xe2x80x94C(O)xe2x80x94Ar1, xe2x80x94S(O)2xe2x80x94Ar1, xe2x80x94R9, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94S(O)2xe2x80x94NH2, xe2x80x94C(O)xe2x80x94R9, xe2x80x94C(O)xe2x80x94Oxe2x80x94R9, xe2x80x94S(O)2xe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R10)(Ar1), xe2x80x94S(O)2xe2x80x94N(R10)(Ar1), xe2x80x94C(O)xe2x80x94N(R10)(R9), or xe2x80x94S(O)2xe2x80x94N(R10)(R9);
each R9 is a C1-6 straight or branched alkyl group optionally singly or multiply substituted with xe2x80x94OH, xe2x80x94F, xe2x95x90O or Ar1, wherein any R9 may be substituted with a maximum of two Ar1;
each R10 is independently selected from xe2x80x94H or C1-6 straight or branched alkyl;
R13 is xe2x80x94H, xe2x80x94Ar1, xe2x80x94R9, xe2x80x94T1xe2x80x94R9 or xe2x80x94(CH2)1-3xe2x80x94T1xe2x80x94R9;
each Ar1 is a cyclic group independently selected from a monocyclic, bicyclic or tricyclic aryl group containing 6, 10, 12 or 14 carbon atoms; a monocyclic, bicyclic or tricyclic cycloalkyl group containing between 3 and 15 carbon atoms, said cycloalkyl group being optionally benzofused; or a monocyclic, bicyclic or tricyclic heterocycle group containing between 5 and 15 ring atoms and at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, or xe2x80x94NHxe2x80x94, wherein said heterocycle group optionally contains one or more double bonds and optionally comprises one or more aromatic rings;
Ar3 is a cyclic group selected from phenyl, a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring, wherein said heteroaromatic rings comprise from 1-3 heteroatom groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x95x90Nxe2x80x94, or xe2x80x94NHxe2x80x94;
wherein each Ar1 or Ar3 is optionally singly or multiply substituted at any ring atom by xe2x80x94NH2, xe2x80x94C(O)xe2x80x94OH, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, 
xe2x80x83or xe2x80x94Q1; and
each Q1 is independently selected from xe2x80x94Ar1, xe2x80x94R9, xe2x80x94T1xe2x80x94R9, or (CH2)1-3xe2x80x94T1xe2x80x94R9; provided that when xe2x80x94Ar1 is substituted with a Q1 which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with Q1.
Preferably, the process of this invention is used as a step in the synthesis of a compound of formula I, wherein n is 1 and m is 2.
In another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula I, wherein R5 is an acyl moiety selected from xe2x80x94C(O)xe2x80x94Ar1, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94R9, xe2x80x94C(O)xe2x80x94Oxe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R10)(Ar1), or xe2x80x94C(O)xe2x80x94N(R10)(R9).
In yet another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula I, wherein X1 is CH; each J is H; mxe2x80x2 is 1; T is xe2x80x94COOH or a biosteric replacement for xe2x80x94COOH; g is 0; and R3 is xe2x80x94C(O)xe2x80x94R13.
In the most preferred embodiment of using the process of this invention as a step in the synthesis of a compound of formula I, said compound has the structure: 
Alternatively, the process of this invention may be used as a step in the synthesis of a compound of the formula (II): 
wherein:
Z is selected from 
p is 1 or 2;
each R5xe2x80x2 is independently selected from xe2x80x94C(O)xe2x80x94R10xe2x80x2, xe2x80x94C(O)Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)xe2x80x94N(R10xe2x80x2)(R10xe2x80x2), xe2x80x94S(O)2xe2x80x94R9xe2x80x2, xe2x80x94S(O)2xe2x80x94NHxe2x80x94R10xe2x80x2, xe2x80x94C(O)xe2x80x94CH2xe2x80x94Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94R10xe2x80x2, xe2x80x94R9xe2x80x2, xe2x80x94H, xe2x80x94C(O)C(O)xe2x80x94OR10xe2x80x2, or xe2x80x94C(O)C(O)xe2x80x94N(R9xe2x80x2)(R10xe2x80x2);
each R9xe2x80x2 is independently selected from xe2x80x94Ar1 or a xe2x80x94C1-6 straight or branched alkyl group optionally substituted with Ar1, wherein the xe2x80x94C1-6 alkyl group is optionally unsaturated;
each R10xe2x80x2 is independently selected from xe2x80x94H, xe2x80x94Ar1, a xe2x80x94C3-6 cycloalkyl group, or a xe2x80x94C1-6 straight or branched alkyl group optionally substituted with Ar3xe2x80x2, wherein the xe2x80x94C1-6 alkyl group is optionally unsaturated;
R13xe2x80x2 is selected from H, Ar1, or a C1-6 straight or branched alkyl group optionally substituted with Ar1, xe2x80x94CONH2, xe2x80x94OR5xe2x80x2, xe2x80x94OH, xe2x80x94OR9xe2x80x2, or xe2x80x94CO2H;
each R51 is independently selected from R9xe2x80x2, xe2x80x94C(O)xe2x80x94R9xe2x80x2, xe2x80x94C(O)xe2x80x94N(H)xe2x80x94R9xe2x80x2, or two R51 taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94;
each R21 is independently selected from xe2x80x94H or a xe2x80x94C1-6 straight or branched alkyl group;
Y2 is xe2x80x94H2 or xe2x95x90O
each Ar1 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, SO2, xe2x95x90Nxe2x80x94, and xe2x80x94NHxe2x80x94, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by xe2x80x94Q1;
each Q1 is independently selected from the group consisting of xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Cl, xe2x80x94F, xe2x80x94Br, xe2x80x94I, xe2x80x94NO2, xe2x80x94CN, xe2x95x90O, xe2x80x94OH, -perfluoro C1-3 alkyl, R5xe2x80x2, xe2x80x94OR5xe2x80x2, xe2x80x94NHR5xe2x80x2, OR9xe2x80x2, xe2x80x94N(R9xe2x80x2)(R10xe2x80x2), R9xe2x80x2, xe2x80x94C(O)xe2x80x94R10xe2x80x2, and 
provided that when xe2x80x94Ar1 is substituted with a Q1 group which comprises one or more additional xe2x80x94Ar1 groups, said additional xe2x80x94Ar1 groups are not substituted with another xe2x80x94Ar1.
Preferably, the process of this invention is used as a step in the synthesis of a compound of formula II, wherein Y2 is O and R21 is H.
In another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula II, wherein R5xe2x80x2 is selected from xe2x80x94C(O)xe2x80x94R10xe2x80x2, xe2x80x94C(O)Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)xe2x80x94N(R10xe2x80x2)(R10xe2x80x2), xe2x80x94C(O)xe2x80x94CH2xe2x80x94Oxe2x80x94R9xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94R10xe2x80x2, xe2x80x94C(O)C(O)xe2x80x94OR10xe2x80x2, or xe2x80x94C(O)C(O)xe2x80x94N(R9xe2x80x2)(R10xe2x80x2).
In yet another preferred embodiment, the process of this invention is used as a step in the synthesis of a compound of formula II, wherein Z is 
p is 1 and R51 is selected from xe2x80x94Ar1, xe2x80x94C1-6 straight or branched alkyl or xe2x80x94C1-6 straight or branched alkyl substituted with Ar1.
In the most preferred embodiment of using the process of this invention as a step in the synthesis of a compound of formula II, said compound has the structure: 
In the synthesis of these inhibitors, R1 contains an amino protecting substituent. Preferably R1 
The conversion of compound G to compounds of formula I or II is set forth in Scheme 3 below. 
In Scheme 3, R2-R5 C, g, J, m, mxe2x80x2, n, X1, Z, and T are as defined above. Gxe2x80x2 is optionally substituted at any ring carbon with one or more substituents selected from C1-6 straight or branched alkyl, C2-4 straight or branched alkenyl or alkynyl, Oxe2x80x94[C1-6 straight or branched alkyl], Oxe2x80x94[C2-6 straight or branched alkenyl or alkynyl], oxo, halo or Q1;
Each of these steps is well known in the art. Compounds of formula J may be readily obtained from compound Hxe2x80x2 by deprotection of the amine. When R1 is 
the removal of the amine protecting substituent is typically carried out with hydrazine. Coupling of amine J to R5 is achieved with standard coupling reagents, such as EDC, DCC or acid chloride to afford compound K.
Depending upon the nature of R2, its hydrolysis may be achieved with an acid (when R2 is t-butyl), a hydroxide (when R2 is any other alkyl, alkenyl, alkynyl, or Ar) or hydrogenolysis (when R2 is an Ar-substituted alkyl, alkenyl or alkynyl). This produces the corresponding acid L from the ester K.
The acid L is then coupled using standard coupling conditions to the amine 
to afford a compound of formula I or to the amine xe2x80x94NHxe2x80x94Z to afford a compound of formula II. These standard coupling conditions include, but are not limited to, EDC, DCC, or acid chloride-mediated coupling.
According to another embodiment, the invention provides a process for converting a compound of formula G to a compound of formula I or II comprising the steps of:
a) combining compound G with an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme, THF, or CCl4;
b) adding less than about 0.2 equivalents of DMF;
c) adjusting the temperature of the resulting mixture to between 20xc2x0 C. and 100xc2x0 C.;
d) adding about 2 or more equivalents of SOCl2 to said mixture over a period of between 2 and 24 hours;
e) removing of the amine protecting group from compound H to form amine J;
f) coupling of R5 to amine J to form ester K;
g) deprotecting ester K to form acid L; and
h) coupling acid L to:
i) 
xe2x80x83to form a compound of formula I; and
ii) xe2x80x94NHxe2x80x94Z to form a compound of formula II.